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Chlamydia Trachomatis and Neisseria Gonorrhoeae Khalil G. Ghanem, MD Johns Hopkins University
A Brief Aside Several of the pictures used in this talk are not my own, but those of individuals who, over the years, have kindly given me copies to use Occasionally, some were obtained from the internet The figures and charts in the epidemiology section are from the 2005 CDC STD Surveillance Report which can be found at the following URL: http://www.cdc.gov/std/stats/trends2005.htm 3
Section A Chlamydia Trachomatis
Chlamydia Trachomatis: Pathogenesis Obligate intracellular bacterium Has DNA and RNA, bacterial ribosomes, gram-negative-like cell wall Deficient in endogenous ATP production Has a dimorphic developmental cycle, which happens in an intracellular cytoplasmic inclusion Susceptible to antibiotics 5
Serological Classification A,B, Ba, C (Trachoma) D-K (genitourinary and ocular infections) L1-L3 (lymphogranuloma venereum) 6
Clinical Manifestations (D-K Serotypes): Men Urethritis Discharge classically may be asymptomatic Epididymitis 70% due to CT 7
Clinical Manifestations (D-K Serotypes): Women Cervicitis Majority no signs or symptoms If present, signs include... Discharge, ectopy, edema, induced bleeding 30-50% have mucopurulent cervicitis (>30 PMNs per oil immersion field) Pelvic Inflammatory Disease (PID) 8
Clinical Manifestations: Men and Women Proctitis Caused by direct inoculation from unprotected anal sex Serovar D-K or LGV types Symptoms may include... Rectal bleeding and pain Mucous discharge Diarrhea 9
Lymphogranuloma Venereum Worldwide distribution but higher prevalence in tropical and subtropical regions Endemic in Africa, India, SE Asia, the Caribbean, and Brazil Strains are more invasive Cause thrombolymphangitis Early disease transient genital ulcer, buboes, inflammation; rectal pain/bleeding Late disease abscesses, fistulas, genital elephantiasis, frozen pelvis, and rectal strictures 10
Trachoma: Serovars A, B, Ba, C Trachoma is a chronic keratoconjunctivitis Active disease occurs most commonly in preschool-aged children, with the highest prevalence in those children three to five years old Disease transmission occurs primarily between children and the women who care for them Repeated episodes of reinfection within the family cause chronic follicular conjunctival inflammation (active trachoma) resulting in corneal abrasions, corneal scarring and, ultimately, blindness Most common cause of preventable blindness worldwide In the U.S. Endemic once in North America and Europe but has disappeared with improved living standards Internationally Trachoma is endemic in Africa, Asia, the Middle East, and Aboriginal communities in Australia Worldwide, 360 million people are affected 11
Chlamydia: Diagnosis Cell culture sensitivity no more than 80% and invasive Non-amplified molecular tests (EIA, DFA) sensitivity up to 85% Amplified molecular tests [nucleic acid amplification tests (NAATs)] Gold standard; can be performed on genital swabs (cervical, urethral, or vaginal) and on urine (i.e., less invasive ) Sensitivity > 90% Introduced in the mid 1990s Interesting Question: How do we assess diagnostic accuracy of a test that is more sensitive than the gold standard? 12
Section B Chlamydia Trachomatis: Epidemiology
Overview Most commonly reported infectious disease in the U.S. (976,445 cases reported in 2005 to the CDC) Approximately 5%-14% of routinely screened females aged 16-20 years and 3%-12% of women aged 20-24 years are infected with chlamydia 335 commercial health maintenance organizations (HMOs) and point-of-service (POS) plans and 92 Medicaid HMO and POS plans reported chlamydia screenings These data accounted for 83% of enrollees in commercial HMO and POS plans and up to 30% of enrollees in Medicaid HMO and POS plans in the United States during this period MMWR October 29, 2004/53(42); 983-985 14
Chlamydia Rates: United States, 1986 2005 The 2005 rates for the United States were calculated by dividing the number of cases reported from each area in 2005 by the estimated area-specific 2004 population STD Surveillance 2005. CDC. 15
Need Title Adam/Andy can you please give me a title for this slide? Note trends adjusted for changes in laboratory test method and associated increases in test sensitivity Source: Regional Infertility Prevention Projects. CDC. 16
Chlamydia Rates by Region STD Surveillance 2006. CDC. 17
Chlamydia Rates by Race STD Surveillance 2006. CDC. 18
Female Chlamydia Rates, 2005 3500 Cases per 100,000 Population 3000 2500 2000 1500 1000 500 0 10 to 14 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 45 to 54 55 to 64 65+ Age 19
Epidemiology: Summary The increase in reported chlamydia infections during the last 10 years is due to the following: The expansion of chlamydia screening activities Increasingly sensitive diagnostic tests Increasing emphasis on case reporting from both providers and laboratories Improvements in the information systems for reporting Chlamydia screening and reporting are likely to expand further in response to the recently implemented Health Plan Employer Data and Information Set (HEDIS) measure for chlamydia screening of sexually active women 15 through 25 years of age who receive medical care through managed care organizations 20
FYI: CDC Reporting Reporting of Chlamydia Cases Trends in chlamydia morbidity reporting from many areas are more reflective of changes in diagnosis and reporting of cases rather than actual trends in disease incidence. Cases and rates of reported chlamydia in sex-specific tables are underestimated due to some reported cases with unknown sex. Despite problems with underreporting, it is important to publish available data to emphasize the large numbers of cases of chlamydia being detected in the United States. As areas develop chlamydia prevention and control programs, including improved surveillance systems to monitor trends, the data should improve and become more representative of true trends in disease. Source: CDC STD Surveillance 2005: Appendix 21
Section C Chlamydia Trachomatis: Treatment and Screening
Recommended Regimens: CT Recommended Regimens Azithromycin 1 g PO or... Doxycycline 100 mg PO BID for seven days Alternative Regimens Seven day course of... Erythromycin base 500 mg PO QID or... Erythromycin ethylsuccinate 800 mg QID or... Ofloxacin 300 mg PO BID 23
Other Considerations for Chlamydia Treatment Re-screen women for CT three to four months after treatment Screen sexually active women < = 25 years-old and high-risk women > 25 years old Refer all sex partners in the last 60 days for evaluation, testing, and therapy No sex until patient AND partner/partners are cured 24
Chlamydia Trachomatis: Infection and Re-Infection in 12-19 Year-Old Adolescent Women 3,202 sexually active women followed for 33 months Chlamydia infection in 24% of 1st visits and 14% of repeat visits Median time positive test 1st positive 7.2 months Repeat positive 6.3 months Screen sexually active adolescent females every six months Source: Burstein, et al. (1998). JAMA; 280: 521-526 25
Does Screening Lead to Better Outcomes? Prospective study in group health, Seattle 2,607 reproductive-age women From 1990 1992 (did not use NAATs) 1,009 randomized to screening intervention (but only 645 got tested) 1,598 usual care (no active intervention) Outcome number of cases of PID in each group (ITT analysis) Source: Scholes, D., NEJM (1996); 334: 1362-1366 26
Prevention of PID: Screening for Chlamydial Infection Screening Usual Care Odds Ratio Number of Cases of PID 9 33 0.42 (0.20-0.89) Per 10,000 woman-months O.R. adjusted age, marital status, douching Source: Scholes, D. et al. (1996). NEJM, 334: 1362-1366 27
Section D Neisseria Gonorrhea
Neisseria Gonorrhoeae (GC) Gram-negative diplococcus Fastidious requires hemoglobin, CO 2 Only causes disease in humans No animal host Causes infection in columnar epithelial surfaces Multiple types implications for vaccine 29
Gonococcal Syndromes Men urethritis, epididymitis Women cervicitis, salpingitis Men and women proctitis, pharyngitis Newborns ophthalmia, pneumonia Unusual disseminated infection, adult ophthalmia, endocarditis, meningitis 30
Urethritis and Cervicitis Urethritis Mostly seen in men [although urethritis may accompany cervicitis in women (~30%)] Symptoms discharge of pus from the urethra & dysuria (pain on urination). Purulent discharge seen in > 80% of men with GC urethritis Cervicitis 30-50% of women may be asymptomatic Symptoms discharge, pruritus (itching), lower abdominal pain, dysuria, dyspareunia (painful intercourse) Several other diseases can mimic GC symptoms chlamydia, herpes, trichomoniasis, BV, MPC 31
GC and HIV Retrospective and prospective studies demonstrate increased risk of HIV TRANSMISSION (HIV viral load in semen of GC infected men increases dramatically) and... ACQUISITION (increased number of immune cells in presence of GC infection) What are some potential problems with these studies? 1. Behavioral confounding 2. Selection bias 3. Temporal bias Think about other different types of biases in retrospective and prospective studies 32
GC Diagnosis Gram s stain has about 90% sensitivity in SYMPTOMATIC men Sensitivity much lower in symptomatic women (~50%) and asymptomatic men and women (< 50%) Specificity is about 95% in men, but lower in women Culture is still the gold standard; sensitivity > 90% and specificity > 99% (gender differences in sensitivity) Non-amplified molecular tests (EIA, etc.) Amplified molecular tests NAATs (not FDA cleared for rectal and oropharyngeal samples) 33
Symptoms (or Lack of Symptoms) 90 80 Percent Asymptomatic 70 60 50 40 30 20 10 Men Women 0 Urethra Rectum Pharynx Cervix Rectum Urethra Any Gonorrhea Chlamydia Herpes 34
Section E The Epidemiology of Neisseria Gonorrhoeae
Overview Gonorrhea is the second most commonly reported notifiable disease in the United States (339,593 cases reported to the CDC in 2005) From 1975-1997, U.S. gonorrhea rates declined 74.3% following implementation of the national gonorrhea control program in the mid-1970s However, in 2005, rates increased slightly from 2004 Rate increases or decreases may be masked by the following: Changes in screening practices (affected by simultaneous testing for chlamydia) Use of diagnostic tests with different sensitivities Changes in reporting practices 36
Gonorrhea Rates: United States 1941 2005 and the Healthy People 2010 Target STD Surveillance 2006. CDC 37
Gonorrhea Rates by State: United States (2005) STD Surveillance 2006. CDC 38
Gonorrhea Rates by Sex: United States, 1986 2005 STD Surveillance 2006. CDC 39
Gonorrhea Rates by Race and Ethnicity: U.S., 1981 2004 STD Surveillance 2006. CDC 40
Gonorrhea Positivity by Age STD Surveillance 2006. CDC 41
Section F Neisseria Gonorrhoeae: Treatment and Drug Resistance
Therapy for Uncomplicated GC of the Cervix, Urethra and Rectum Cefixime 400 mg orally Ceftriaxone 125 mg intramuscular Ciprofloxacin 500 mg orally Ofloxacin 400 mg orally PLUS Doxycycline 100 mg orally twice a day x 1 week OR Azithromycin 1 gm orally x1 43
Partner Treatment Modalities None DIS (disease intervention specialists) Patient initiated REFERRAL of partners Novel method patient initiated TREATMENT of partners Source: Golden, et al. (2005). N Engl J Med. Feb 17; 352(7):676-85 44
Antimicrobial Resistance STD Surveillance 2005. CDC 45
Quinolone Resistant Gonorrhea (QRNG) Rapidly increasing especially in the Pacific Basin Change in treatment guidelines for the West Coast Quinolones recommended only since 1989 Probably due to antibiotic overuse/misuse 46
Fluoroquinolone-Resistant Strains in the U.S. STD Surveillance 2005. CDC 47
GC: Summary of Major Epidemiological Trends Gonorrhea maintained in core groups Disproportionate impact on minorities Increases in gay men Emerging quinolone resistance Repeater impact Facilitate HIV infection 48
Future GC Issues that Need to be Addressed How much longer can we use fluoroquinolones? Will NAATs become the new gold standard in diagnosing neisseria gonorrhoeae? How will we follow susceptibility patterns of the organisms without culture testing? Where s the vaccine? 49